In the first study to compare all available IVF treatments and the risk
of neurodevelopmental disorders in children, researchers find that IVF
treatments for the most severe forms of male infertility are associated
with an increased risk of intellectual disability and autism in
children.

Autism and intellectual disability remain a rare outcome of IVF, and
whilst some of the risk is associated with the risk of multiple births,
the study provides important evidence for parents and clinicians on the
relative risks of modern IVF treatments.

Published in JAMA today, the study is the largest of its
kind and was led by researchers at King's College London (UK),
Karolinska Institutet (Sweden) and Mount Sinai School of Medicine in New
York (USA).

By using anonymous data from the Swedish national registers,
researchers analysed more than 2.5 million birth records from 1982 and
2007 and followed-up whether children had a clinical diagnosis of autism
or intellectual disability (defined as having an IQ below 70) up until
2009. Of the 2.5m children, 1.2% (30,959) were born following IVF. Of
the 6,959 diagnosed with autism, 103 were born after IVF; of the 15,830
with intellectual disability, 180 were born after IVF. Multiple
pregnancies are a known risk factor for pre-term birth and some
neurodevelopmental disorders, so the researchers also compared single to
multiple births.

Sven Sandin, co-author of the study from King's College London's
Institute of Psychiatry says: "IVF treatments are vastly different in
terms of their complexity. When we looked at IVF treatments combined, we
found there was no overall increased risk for autism, but a small
increased risk of intellectual disability. When we separated the
different IVF treatments, we found that 'traditional' IVF is safe, but
that IVF involving ICSI, which is specifically recommended for paternal
infertility is associated with an increased risk of both intellectual
disability and autism in children."

Compared to spontaneous conception, children born from any IVF
treatment were not at an increased risk of autism, but were at a small
increased risk of intellectual disability (18% increase -- from 39.8 to
46.3 per 100,000 person years). However, the risk increase disappeared
when multiple births were taken into account.

Secondly, the researchers compared all 6 different types of IVF
procedures available in Sweden -- whether fresh or frozen embryos were
used; if intracytoplasmic sperm injection (ICSI) was used, and if so,
whether sperm was ejaculated or surgically extracted. Developed in 1992,
ICSI is recommended for male infertility and is now used in about half
of all IVF treatments. The procedure involves injecting a single sperm
directly into an egg, rather than fertilization happening in a dish, as
in standard IVF.

Children born after IVF treatments with ICSI (with either fresh or
frozen embryos) were at an increased risk of intellectual disability
(51% increase -- 62 to 93 per 100,000). This association was even higher
when a preterm birth also occurred (73% increase -- 96 to 167 per
100,000). Even when multiple and pre-term births were taken into
account, IVF treatment with ICSI and fresh embryos was associated with
an increased risk of intellectual disability (66% increase for singleton
birth, term birth following ICSI with fresh embryos- 48 to 76 per
100,000).

Children born after IVF with ICSI using surgically extracted sperm
and fresh embryos were at an increased risk of autism (360% increase --
29 to 136 per 100,000) but the association disappeared when multiple
births were taken into account.

Dr Avi Reichenberg, who led the study from King's College London's
Institute of Psychiatry and Mount Sinai School of Medicine, adds: "Our
study shows that treatments developed to manage male infertility are
associated with an increased risk for developmental disorders in the
offspring. The exact mechanism is unclear, but there are a number of
risk factors, from selection of IVF procedures, to multiple embryos, and
to preterm birth. Whilst intellectual disability or autism remain a
rare outcome for IVF, being aware of the increased risk associated with
specific types of IVF means offspring at risk can be identified and
potentially monitored for developmental disorders, ensuring they receive
early detection and appropriate support and care."

Dr Karl-Gösta Nygren, co-author from Karolinska Institutet, says:
"It's important to remember that the majority of children are born
perfectly healthy following IVF. Our study provides much needed
information for parents and clinicians on the relative risks of modern
IVF treatments, enabling them to make the most informed choice possible.
Our study also provides further evidence for the need to minimize
multiple embryo transfer. However, more research is needed to elucidate
the reasons behind our findings."

The authors add that within the context of this study, it was not
possible to determine the exact mechanism by which IVF treatment
following ICSI is associated with an increased risk of intellectual
disability. However, the authors did extend their study to consider
possible explanations for the increased risk, such as parental age,
temporal trend, hormonal treatment or length of infertility problems,
but found no further explanations to the results.

The study was conducted in Sweden but the findings are applicable to
most countries where IVF and ICSI are used but there may be differences
in choice of procedure.